Traumatic injury to the central nervous system (CNS) results in a host of cellular reactions. Responses at the injury site are directed towards phagocytosis of debris and development of a glial scar, and have been well characterized. Immune markers such as the major histocompatibility complex (MHC) antigens, normally not present in the brain, appear on the astrocytes and microglia. The appearance of the MHC antigens and the proliferation of the cellular elements are likely under the control of potent regulators of the immune system known as cytokines (interferons, interleukins, and others). The immunological responses at sites distal to the injury site are less well characterized, though they may be important in neuronal survival or death. Injury that results in axotomy causes a series of reactions in those neurons whose axons are injured, ranging from changes in metabolic activity to atrophy to death. Neuronal loss may be prevented by target derived neurotrophic factors. Recent reports suggest that axotomy of neurons with extrinsic projections leads to activation of the immune system, as suggested by expression of MHC antigens on astrocytes and microglia surrounding the neuron. MHC antigens disappear as target reinnervation occurs. Target derived neurotrophic factors may play a key role in the regulation of the immune system. This proposal intends to: 1) characterize the immune response (MHC expression, cytokine release) in the rat forebrain after fimbria/fornix axotomy, then perturb this response with nerve growth factor or cytokine receptor blockers; 2) describe nerve growth factor effects on immune expression of astroglial cells in vitro; 3) examine astroglial immune response after neuron injury or ablation in hippocampal slice culture using a "photon scalpel". As part of the theme "Repair and Response Mechanisms", this project queries the role of the immune system in 1) mechanisms underlying neurotrophic factor effects and 2) neuron-glial interactions. It relies on technology from collaborators in Projects 1 and 7.